CN1994289B - Application of dibenzocyclootadiene lignans in preparation of tyrosine-inhibiting medicine - Google Patents

Application of dibenzocyclootadiene lignans in preparation of tyrosine-inhibiting medicine Download PDF

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CN1994289B
CN1994289B CN2006100489051A CN200610048905A CN1994289B CN 1994289 B CN1994289 B CN 1994289B CN 2006100489051 A CN2006100489051 A CN 2006100489051A CN 200610048905 A CN200610048905 A CN 200610048905A CN 1994289 B CN1994289 B CN 1994289B
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benzene ring
lignanoid
couplet benzene
ring octadiene
wuweizisu
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CN1994289A (en
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胡汛
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Gao Chenyong
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Ningbo Yingnuo Pharmaceutical Technology Co Ltd
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Abstract

The invention relates to an application of biphenyl cyclo-octadiene lignans for preparing tyrosinase restrainer, wherein said drug is cancer treater or tyrosinase-abnormal treater. Said drug can be the monomer of biphenyl cyclo-octadiene lignans, or the mixture of biphenyl cyclo-octadiene lignans. The invention can improve sensitivity of tyrosinase restrainer.

Description

The application of couplet benzene ring octadiene lignanoid in preparation tyrosine-kinase enzyme inhibitor thing
(1) technical field
The present invention relates to couplet benzene ring octadiene the lignanoid application in preparation tyrosine-kinase enzyme inhibitor thing, the especially application in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing.
(2) background technology
Current, tyrosine kinase has been widely accepted the target spot into oncotherapy.The gene of nearly 90 tyrosine kinase in the human genome.In tumor, tyrosine kinase often has unusually.Imatinib mesylate (English gleevec by name, or imatinib, or STI571) is a kind of inhibitor at unusual tyrosine kinase in the tumor by Novartis Co.,Ltd's exploitation.This medicine can suppress tyrosine kinase unusual in the kinds of tumors, and is used for the treatment of kinds of tumors, as leukemia, stomach mesenchymoma, glioblastoma multiforme, sarcoma, pulmonary carcinoma or the like.Different yet the therapeutic effect of imatinib mesylate is answered patient, some patient is responsive to this medicine, and some patient is not too responsive.Also there are same problem in other tyrosine-kinase enzyme inhibitor thing such as gefitinib, Chinese mugwort sieve for Buddhist nun, erbitux or the like.Therefore, need to increase the hypersitization medicine of tyrosine-kinase enzyme inhibitor thing clinically.The research of external more existing imatinib mesylate sensitizers.
Couplet benzene ring octadiene lignanoid is a Fructus Schisandrae Chinensis: the main component in the dry mature fruit of magnoliaceae schisandra Schisandra chinensis (Turcz.) Baill. or Magnoliacea plant schisandra chinensis Schisandra sphenanthera Rehd.et Wils., Fructus Schisandrae Chinensis is listed in top grade in Shennong's Herbal, effect with convergence, astringent or styptic treatment for spontaneous sweating, supplementing QI for promoting the production of body fluid, kidney calming, it is traditional Chinese medical science strengthening by means of tonics medicine commonly used, have multiple pharmacological effect, but do not see its report the inhibition medicine enhanced sensitivity of tyrosine kinase such as imatinib mesylate.
(3) summary of the invention
The present invention is for the application of couplet benzene ring octadiene lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing is provided.
For reaching goal of the invention, the technical solution used in the present invention is:
The application of couplet benzene ring octadiene lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing.Described tyrosine-kinase enzyme inhibitor thing is treated agent or the unusual Remedies for diseases of tyrosine kinase for the tumor smelting.
Described couplet benzene ring octadiene lignanoid structure is suc as formula shown in the I:
In the formula, R 1, R 2, R 5, R 6Be respectively hydroxyl or methoxyl group, perhaps, R 1With R 2, R 5With R 6Not ring formation or R separately 1With R 2, R 5With R 6Form the alcoxyl ring separately;
R 3For one of following: 1.-O-CH 32.-OH;
Figure G2006100489051D00022
R 4For one of following: 1.-O-CH 32.-OH;
Figure G2006100489051D00023
R 7For one of following: 1.-H; 2.-OH;
Figure G2006100489051D00024
Figure G2006100489051D00025
R 8, R 9One of it is following respectively to do for oneself: 1.-and H; 2.-OH;
R 10For one of following: 1.-H; 2.-OH;
Figure G2006100489051D00032
Figure G2006100489051D00033
Perhaps, R 7With R 10Be linked to be oxo bridge, R 1～R 6, R 8, R 9Definition as mentioned above;
Perhaps, R 3With R 7Form the acyl-oxygen ring, R 1, R 2, R 4～R 6, R 8～R 10Definition as mentioned above.The said structure formula mainly comprises following material according to each substituent group definition:
Figure G2006100489051D00051
Figure G2006100489051D00091
Figure G2006100489051D00101
Figure G2006100489051D00111
Figure G2006100489051D00121
Further, described couplet benzene ring octadiene lignanoid structural formula is as follows:
Figure G2006100489051D00131
In the formula, R 1, R 2, R 5, R 6Be respectively hydroxyl or methoxyl group, perhaps, R 1With R 2, R 5With R 6Not ring formation or R separately 1With R 2, R 5With R 6Form the alcoxyl ring separately:
R 7For one of following: 1.-H; 2.-OH;
R 8, R 9One of it is following respectively to do for oneself: 1.-and H; 2.-OH;
R 10For one of following: 1.-H; 2.-OH;
Figure G2006100489051D00134
Preferably, described couplet benzene ring octadiene lignanoid is one of following formula:
1. wuweizisu A; 2. wuweizisu B; 3. schisandrin C; 4. schizantherin A; 5. schizantherin B; 6. schizantherin C; 7. schizantherin D; 8. schizantherin E; 9. 10. wuweizi alcohol B of wuweizi alcohol A.
Described antitumor tyrosine-kinase enzyme inhibitor thing is one of following: imatinib mesylate (gleevec, or imatinib, or STI571), gefitinib (gefinitib, Iressa, ZD1839), erlotinib (erlotinib, Tarceva), erbitux (cetuximab, Erbitux), trastu zumad (trastuzumab), SU5416 (semaxinib), SU-5402, PTK787 (vatalanib), SU11248 (sutent), BAY43-9006 (sorafenib), SU101 (leflunomide), GW-572016 (lapatinib), CI-1033 (canertinib), AZD6474, PK1166, SKBR3, BT-474, SU6668, CI-1033, PKC412, MLN518, CEP-701, PD0173074, SMS-354825, D816X, ABX-EGF, 2C4, CT52923, Bevacizumab, PD180970, PD173955, SKI606, BMS354825, AZD0530, AP23464, CGP76030, AMN107.
Described hypersitization medicine also contains drug excipient or carrier, can be made into one of following dosage form:
1. injection; 2. tablet; 3. capsule; 4. granule; 5. slow releasing agent.
Described described hypersitization medicine can be the monomer of described couplet benzene ring octadiene lignanoid, also can be the mixture of described couplet benzene ring octadiene lignanoid.
The present invention is the further clear and definite sensitization of couplet benzene ring octadiene lignanoid to tyrosine-kinase enzyme inhibitor thing has good potential applicability in clinical practice.
(4) specific embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1: couplet benzene ring octadiene lignanoid strengthens the drug effect that imatinib mesylate kills the leukaemia
Experimental technique: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.Human leukemia cell line Ku812 and K562 (U.S. ATCC company).K562 or Ku812 cultivate respectively in containing the RPMI-1640 culture fluid of 10% calf serum, be inoculated in the 24 porocyte culture plates, every porocyte is 40,000 cells, adds certain a certain amount of couplet benzene ring octadiene lignanoid then, adds the imatinib mesylate of variable concentrations more separately.Cultivate after 3 days, count the cell number in each hole, obtain half-inhibition concentration IC then with cell streaming instrument (FACScan, U.S. Becton Dickinson) 50
Experimental result:
Ku812 and K562 are the chronic myelogenous leukemia cell strain, have unusual tyrosine (Bcr-abl) kinases.Imatinib mesylate suppresses intracellular unusual tyrosine kinase, therefore can kill the leukaemia.
The strain of Ku812 chronic myelogenous leukemia cell, be divided into four groups, each is organized every hole and adds wuweizisu B 0 μ g/ml respectively, 5 μ g/ml, 10 μ g/ml, 20 μ g/ml, each hole adds separately that imatinib mesylate to final concentration is 0,6,12,25,50,100ng/ml again under identical schizandrin concentration, tries to achieve half-inhibition concentration IC separately 50, presentation of results, couplet benzene ring octadiene lignanoid can significantly strengthen the drug effect of imatinib mesylate to Ku812 and K562.
Table 1 and table 2 explanation, wuweizisu B strengthens the drug effect of imatinib mesylate to Ku812.
Table 1, wuweizisu B enhancing imatinib mesylate are dose dependent to the drug effect of Ku812
Wuweizisu B (μ g/ml) IC 50(imatinib mesylate ng/ml) The enhanced sensitivity multiple
0 37±4 1
5 19±2* 1.9
10 12±3* 3.1
20 8±1* 4.6
* compare with matched group that there were significant differences, p＜0.05.
Following experiment is to get 42 hole Ku812 chronic myelogenous leukemia cell strains, be divided into 7 groups, one group is blank, six groups of wuweizisu A, wuweizisu B, schisandrin C, schizantherin A wuweizi alcohol A, wuweizi alcohol Bs that respectively add final concentration 10 μ g/ml respectively in addition, each hole adds separately that imatinib mesylate to final concentration is 0,6,12,25,50,100ng/ml again in same couplet benzene ring octadiene lignanoid group, tries to achieve half-inhibition concentration IC separately 50
Table 2, couplet benzene ring octadiene lignanoid strengthen the drug effect of imatinib mesylate to Ku812
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(imatinib mesylate ng/ml) The enhanced sensitivity multiple
Contrast 37.2±4.3 1
Wuweizisu A 12.0±3.2* 3.1
Wuweizisu B 11.6±1.2* 3.2
Schisandrin C 11.5±0.8* 3.2
Schizantherin A 11.7±2.3* 3.2
Wuweizi alcohol A 12.1±3.1* 3.1
Wuweizi alcohol B 13.1±2.5* 2.8
* compare with matched group that there were significant differences, p＜0.05.
The strain of K562 chronic myelogenous leukemia cell, be divided into 7 groups, one group is blank, six groups of wuweizisu A, wuweizisu B, schisandrin C, schizantherin A wuweizi alcohol A, wuweizi alcohol Bs that respectively add 10 μ g/ml respectively in addition, in same couplet benzene ring octadiene lignanoid group, add imatinib mesylate to final concentration more separately and be 0,6,12,25,50,100ng/ml, try to achieve half-inhibition concentration IC separately 50
Table 3, couplet benzene ring octadiene lignanoid strengthen the drug effect of imatinib mesylate to K562
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(imatinib mesylate ng/ml) The enhanced sensitivity multiple
Contrast 65±9 1.0
Wuweizisu A 47±4* 1.4
Wuweizisu B 37±2* 1.8
Schisandrin C 36±3* 1.8
Schizantherin A 50±5* 1.3
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(imatinib mesylate ng/ml) The enhanced sensitivity multiple
Wuweizi alcohol A 47±6* 1.4
Wuweizi alcohol B 50±3* 1.3
* compare with matched group that there were significant differences, p＜0.05.
Embodiment 2: couplet benzene ring octadiene lignanoid strengthens the drug effect of imatinib mesylate antagonistic drug cell
Experimental technique: as embodiment 1, different is that used cell is Ku812/r and K562/r, and this 2 strain cell all has resistance to imatinib mesylate, and imatinib mesylate concentration is 0,0.2,0.4,0.8,1.6,3.2,6.4,12.8 μ g/ml.The consumption of different couplet benzene ring octadiene lignanoids as shown in Table, experimental result: the data of table 4 and table 5 show that couplet benzene ring octadiene lignanoid strengthens the drug effect of imatinib mesylate antagonistic drug cell.
Table 4, couplet benzene ring octadiene lignanoid strengthen the drug effect of imatinib mesylate to Ku812/r
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(imatinib mesylate μ g/ml) The enhanced sensitivity multiple
Contrast 6.1±1.3 1.0
Wuweizisu A 1.8±0.3* 3.4
Wuweizisu B 1.5±0.4* 4.1
Schisandrin C 1.6±0.3* 3.8
Schizantherin A 2.1±0.5* 2.9
Wuweizi alcohol A 2.2±0.4* 2.8
Wuweizi alcohol B 2.3±0.6* 2.7
* compare with matched group that there were significant differences, p＜0.05.
Table 5, couplet benzene ring octadiene lignanoid strengthen the drug effect of imatinib mesylate to K562/r
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(imatinib mesylate μ g/ml) The enhanced sensitivity multiple
Contrast 3.8±0.9 1.0
Wuweizisu A 1.6±0.4* 2.4
Wuweizisu B 1.4±0.3* 2.7
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(imatinib mesylate μ g/ml) The enhanced sensitivity multiple
Schisandrin C 1.3±0.5* 2.9
Schizantherin A 1.8±0.4* 2.1
Wuweizi alcohol A 2.1±0.5* 1.8
Wuweizi alcohol B 2.5±0.7* 1.5
* compare with matched group that there were significant differences, p＜0.05.
Embodiment 3, couplet benzene ring octadiene lignanoid strengthen gefitinib, and (gefinitib, Iressa is ZD1839) to the drug effect of KB cell
Experimental technique: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.KB cell (U.S. ATCC company) is cultivated in the DMEM culture fluid of the epidermal growth factor that contains 10% calf serum and 10ng/ml, be inoculated in the 24 porocyte culture plates, every porocyte is 40,000 cells, add a kind of couplet benzene ring octadiene lignanoid then, addition is as shown in table 6, adds the gefitinib of variable concentrations again.Cultivate after 3 days, count the cell number in each hole, obtain half-inhibition concentration IC then with cell streaming instrument (FACScan, U.S. BectonDickinson) 50
Experimental result:
The KB cell is divided into seven groups, one group is blank, six groups of wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol Bs that add final concentration 10 μ g/ml respectively in each hole in addition, in same couplet benzene ring octadiene lignanoid group, add gefitinib to final concentration more separately and be 0,12,25,50,100,200ng/ml, try to achieve half-inhibition concentration IC separately 50, presentation of results, couplet benzene ring octadiene lignanoid can significantly strengthen the drug effect of gefitinib to the KB cell.
The results are shown in Table 6, table 6 explanation, various couplet benzene ring octadiene lignanoid all can significantly strengthen the drug effect of gefitinib.Table 6, couplet benzene ring octadiene lignanoid strengthen the drug effect of gefitinib to the KB cell
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(gefitinib ng/ml) The enhanced sensitivity multiple
Contrast 120±27 1.0
Wuweizisu A 62±13* 1.9
Wuweizisu B 51±15* 2.4
Schisandrin C 64±21* 1.9
Schizantherin A 71±22* 1.7
Wuweizi alcohol A 65±11* 1.8
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(gefitinib ng/ml) The enhanced sensitivity multiple
Wuweizi alcohol B 63±17* 1.9
* compare with matched group that there were significant differences, p＜0.05.
Embodiment 4: couplet benzene ring octadiene lignanoid strengthens drug effect nude mice (female) the oxter inoculation KB cell (2x10 of gefitinib to the KB solid tumor 6), after 10 days, be divided into 7 groups, 10 every group.Group 1 is a blank, and group 2 is a gefitinib, and group 3 adds wuweizisu A for gefitinib, group 4 is for gefitinib adds wuweizisu B, and group 5 is for gefitinib adds schisandrin C, and group 6 adds schizantherin A for gefitinib, group 7 is for gefitinib adds wuweizi alcohol A, and group 8 adds wuweizi alcohol B for gefitinib.Group 2 gefitinib dosage is 200mg/kg every day, the gefitinib dosage of group 3-8 with organize 2 consistently, add the corresponding couplet benzene ring octadiene lignanoid of 100mg/kg.Put to death mice after 14 days, take by weighing tumor and weigh.
Experimental result: the results are shown in Table 7, table 7 explanation, various couplet benzene ring octadiene lignanoid all can increase the drug effect of gefitinib.
Table 7, various couplet benzene ring octadiene lignanoid strengthen the drug effect of gefitinib to the KB solid tumor
Group The experiment group Tumor heavy (g) The heavy suppression ratio (%) of tumor 1
1 Contrast 3.6±0.8
2 Gefitinib 2.4±0.3 33*
3 Gefitinib+wuweizisu A 1.5±0.4 67**
4 Gefitinib+wuweizisu B 1.3±0.3 63**
5 Gefitinib+schisandrin C 1.2±0.5 64**
6 Gefitinib+schizantherin A 1.8±0.4 49**
7 Gefitinib+wuweizi alcohol A 1.7±0.5 54**
8 Gefitinib+wuweizi alcohol B 1.6±0.4 55**
(matched group tumor weight-experimental group tumor is heavy) is divided by matched group tumor heavy * 100%; * compared significant difference with matched group, p＜0.05; * has compared significant difference with the gefitinib group, p＜0.05.
Embodiment 5: couplet benzene ring octadiene lignanoid strengthens erlotinib, and (erlotinib is Tarceva) to the drug effect of KB cell
Experimental technique: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.Oral squamous cell carcinomas KB cell (U.S. ATCC company) is cultivated in containing the DMEM culture fluid of 10% calf serum, be inoculated in the 24 porocyte culture plates, every porocyte is 40,000 cells, adds a kind of couplet benzene ring octadiene lignanoid then, adds the erlotinib of variable concentrations again.Cultivate after 3 days, count the cell number in each hole, obtain half-inhibition concentration IC then with cell streaming instrument (FACScan, U.S. Becton Dickinson) 50
Experimental result:
The KB cell, be divided into seven groups, one group is blank, six groups is wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, the wuweizi alcohol B of 10 μ g/ml at each hole adding final concentration respectively in addition, adding erlotinib to final concentration more separately in same couplet benzene ring octadiene lignanoid group is 0,0.4,0.8,1.6,3.2,6.4,12.8,25.6 μ g/ml, tries to achieve half-inhibition concentration IC separately 50, presentation of results, couplet benzene ring octadiene lignanoid can significantly strengthen the drug effect of erlotinib to the KB cell.
Table 8 explanation, couplet benzene ring octadiene lignanoid can significantly strengthen the drug effect of erlotinib to the KB cell
Table 8, couplet benzene ring octadiene lignanoid strengthen the drug effect of erlotinib to the KB cell
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(erlotinib μ g/ml) The enhanced sensitivity multiple
Contrast 12.3±2.1 1
Wuweizisu A 3.5±0.9* 3.5
Wuweizisu B 3.1±0.6* 4.0
Schisandrin C 2.9±0.5* 4.2
Schizantherin A 3.4±0.5* 3.6
Wuweizi alcohol A 4.2±1.2* 2.9
Wuweizi alcohol B 3.9±0.7* 3.2
*p＜0.05.
Embodiment 6: couplet benzene ring octadiene lignanoid strengthens erbitux, and (cetuximab is Erbitux) to the drug effect of Calus3 cell
Experimental technique: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.Lung carcinoma cell Calus3 cell (U.S. ATCC company) is cultivated in containing the RPMI culture fluid of 10% calf serum, be inoculated in the 24 porocyte culture plates, every porocyte is 10,000 cells, adds a kind of couplet benzene ring octadiene lignanoid then, adds the erbitux of variable concentrations again.Cultivate after 5 days, count the cell number in each hole, obtain half-inhibition concentration IC then with cell streaming instrument (FACScan, U.S. Becton Dickinson) 50
Lung carcinoma cell Calus3 cell, be divided into seven groups, one group is blank, six groups of wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol Bs that respectively add 10 μ g/ml respectively in addition, adding erbitux to final concentration more separately in same couplet benzene ring octadiene lignanoid group is 0,25,50,100,200nM tries to achieve half-inhibition concentration IC separately 50, presentation of results, couplet benzene ring octadiene lignanoid can significantly strengthen the drug effect of erbitux to the KB cell.
Experimental result: table 9 explanation, couplet benzene ring octadiene lignanoid can strengthen erbitux (cetuximab, drug effect Erbitux).
Table 9, couplet benzene ring octadiene lignanoid strengthen the drug effect of erbitux to the Calus3 cell
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(erbitux nM) The enhanced sensitivity multiple
Contrast 152±31 1
Wuweizisu A 75±16* 2.0
Wuweizisu B 62±8* 2.5
Schisandrin C 67±9* 2.3
Schizantherin A 59±12* 2.6
Wuweizi alcohol A 71±5* 2.1
Wuweizi alcohol B 73±21* 2.1
*p＜0.05.
Embodiment 7: couplet benzene ring octadiene lignanoid strengthens the effect of trastu zumad (trastuzumab) BT-474 cell inhibiting
Experimental technique: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.Breast cancer cell BT-474 cell (U.S. ATCC company) is cultivated in containing the RPMI culture fluid of 10% calf serum, be inoculated in the 24 porocyte culture plates, every porocyte is 10,000 cells, each hole adds a kind of couplet benzene ring octadiene lignanoid then, final concentration is 10 μ g/ml, and adding trastu zumad to final concentration in each hole again is 100nM.Group 1 is a blank, and group 2 is a trastu zumad, and group 3 adds wuweizisu A for trastu zumad, group 4 is for trastu zumad adds wuweizisu B, and group 5 is for trastu zumad adds schisandrin C, and group 6 adds schizantherin A for trastu zumad, group 7 is for trastu zumad adds wuweizi alcohol A, and group 8 adds wuweizi alcohol B for trastu zumad.Cultivate after 5 days, count the cell number in each hole, obtain cell survival rate then with cell streaming instrument (FACScan, U.S. Becton Dickinson).
Experimental result: table 10 explanation, couplet benzene ring octadiene lignanoid strengthens trastu zumad (trastuzumab) to the effect of breast cancer cell BT-474 cell inhibiting.
Table 10, couplet benzene ring octadiene lignanoid strengthen trastu zumad (100nM) to the effect of BT-474 cell inhibiting
Group Couplet benzene ring octadiene lignanoid (10 μ g/ml) Cell survival rate (%) 1
1 Contrast 100
2 Trastu zumad 65*
3 Trastu zumad+wuweizisu A 49**
Group Couplet benzene ring octadiene lignanoid (10 μ g/ml) Cell survival rate (%) 1
4 Trastu zumad+wuweizisu B 43**
5 Trastu zumad+schisandrin C 51**
6 Trastu zumad+schizantherin A 46**
7 Trastu zumad+wuweizi alcohol A 61**
8 Trastu zumad+wuweizi alcohol B 63**
1The drug treating group is divided by matched group * 100%; * compare with matched group that there were significant differences, p＜0.05.
Relatively there were significant differences for * and trastu zumad group, p＜0.05.
Embodiment 8, couplet benzene ring octadiene lignanoid strengthen the inhibitory action experimental technique to human umbilical vein's endotheliocyte of SU5416: experimental technique: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.Human umbilical vein's endotheliocyte is cultivated in containing the DMEM culture fluid of 10% calf serum, be inoculated in the 24 porocyte culture plates, every porocyte is 10,000 cells, after 24 hours, add VEGF (vascular endothelial cell growth factor, to 20ng/ml, each hole adds a kind of couplet benzene ring octadiene lignanoid then, adds the SU5416 of variable concentrations again.Cultivate after 3 days, count the cell number in each hole, obtain half-inhibition concentration IC then with cell streaming instrument (FACScan, U.S. Becton Dickinson) 50
Lung carcinoma cell Calus3 cell, be divided into seven groups, one group is blank, six groups of wuweizisu A, wuweizisu B, schisandrin C, schizantherin A wuweizi alcohol A, wuweizi alcohol Bs that respectively add 10 μ g/ml respectively in addition, in same couplet benzene ring octadiene lignanoid group, add separately again SU5416 to final concentration be 0,10,20,40,80,160,320,640nM, try to achieve half-inhibition concentration IC separately 50, presentation of results, couplet benzene ring octadiene lignanoid can significantly strengthen the drug effect of SU5416 to human umbilical vein's endotheliocyte.
Experimental result: table 11 explanation, couplet benzene ring octadiene lignanoid can significantly strengthen the inhibitory action of SU5416 to human umbilical vein's endotheliocyte
Table 11, couplet benzene ring octadiene lignanoid strengthen the inhibitory action of SU5416 to human umbilical vein's endotheliocyte.
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(SU5416nM) The enhanced sensitivity multiple
Contrast 102±11 1
Wuweizisu A 62±13* 1.6
Wuweizisu B 74±7* 1.4
Schisandrin C 59±6* 1.7
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(SU5416nM) The enhanced sensitivity multiple
Schizantherin A 53±8* 1.9
Wuweizi alcohol A 75±10* 1.4
Wuweizi alcohol B 69±13* 1.5
*p＜0.05.
Embodiment 9: couplet benzene ring octadiene lignanoid strengthens the inhibitory action experimental technique of PTK787 to human umbilical vein's endotheliocyte: wuweizisu A, wuweizisu B, schisandrin C, schizantherin A, wuweizi alcohol A, wuweizi alcohol B is mixed with the mother solution of 20mg/ml respectively with DMSO.Human umbilical vein's endotheliocyte is cultivated in containing the DMEM culture fluid of 10% calf serum, be inoculated in the 24 porocyte culture plates, every porocyte is 10,000 cells, after 24 hours, add VEGF (vascular endothelial cell growth factor, to 20ng/ml, each hole adds a kind of couplet benzene ring octadiene lignanoid then, adds the PTK787 of variable concentrations again.Cultivate after 3 days, count the cell number in each hole, obtain half-inhibition concentration IC then with cell streaming instrument (FACScan, U.S. Becton Dickinson) 50Human umbilical vein's endotheliocyte, be divided into seven groups, one group is blank, six groups of wuweizisu A, wuweizisu B, schisandrin C, schizantherin A wuweizi alcohol A, wuweizi alcohol Bs that respectively add 10 μ g/ml respectively in addition, in same couplet benzene ring octadiene lignanoid group, add separately again PTK787 to final concentration be 0,10,20,40,80,160,320,640nM, try to achieve half-inhibition concentration IC separately 50, presentation of results, couplet benzene ring octadiene lignanoid can significantly increase the drug effect of PTK787 to human umbilical vein's endotheliocyte.
Experimental result: table 12 explanation, couplet benzene ring octadiene lignanoid significantly strengthens the inhibitory action of PTK787 to human umbilical vein's endotheliocyte.
Table 12, couplet benzene ring octadiene lignanoid significantly strengthen the inhibitory action of PTK787 to human umbilical vein's endotheliocyte
Couplet benzene ring octadiene lignanoid (10 μ g/ml) IC 50(PTK787nM) The enhanced sensitivity multiple
Contrast 204±46 1
Wuweizisu A 112±25* 1.8
Wuweizisu B 89±15* 2.3
Schisandrin C 78±9* 2.6
Schizantherin A 86±12* 2.4
Wuweizi alcohol A 97±18* 2.1
Wuweizi alcohol B 85±19* 2.4
*p＜0.05.
The experimental result explanation of embodiment 1～9, couplet benzene ring octadiene lignanoid can strengthen the drug effect of various tyrosine-kinase enzyme inhibitor things, illustrates that couplet benzene ring octadiene lignanoid can be used as the sensitizer of tyrosine kinase inhibitor.

Claims (6)

1. the application of couplet benzene ring octadiene lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing,
Described tyrosine-kinase enzyme inhibitor thing is one of following: imatinib mesylate, gefitinib, erlotinib, erbitux, trastu zumad, SU5416, PTK787; Described couplet benzene ring octadiene lignanoid structure is suc as formula shown in the I:
In the formula, R 1, R 2, R 5, R 6Be respectively methoxyl group, perhaps, R 1With R 2, R 5With R 6Not ring formation or R separately 1With R 2, R 5With R 6Form the alcoxyl ring separately;
R 3For-O-CH 3
R 4For-O-CH 3
R 7For-H;
R 8, R 9One of it is following respectively to do for oneself: 1.-and H; 2.-OH;
R 10For one of following: 1.-H; 2.-OH; 3.
2. the application of couplet benzene ring octadiene as claimed in claim 1 lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing is characterized in that described couplet benzene ring octadiene lignanoid structural formula is as follows:
In the formula, R 1, R 2, R 5, R 6The difference methoxyl group, perhaps, R 1With R 2, R 5With R 6Not ring formation or R separately 1With R 2, R 5With R 6Form the alcoxyl ring separately;
R 7For-H;
R 8, R 9One of it is following respectively to do for oneself: 1.-and H; 2.-OH;
R 10For one of following: 1.-H; 2.-OH; 3.
3. the application of couplet benzene ring octadiene as claimed in claim 2 lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing is characterized in that described couplet benzene ring octadiene lignanoid is one of following formula:
1. wuweizisu A; 2. wuweizisu B; 3. schisandrin C; 4. schizantherin A; 5. wuweizi alcohol A; 6. wuweizi alcohol B.
4. the application of couplet benzene ring octadiene lignanoid as claimed in claim 1 in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing is characterized in that described hypersitization medicine also contains drug excipient.
5. the application of couplet benzene ring octadiene as claimed in claim 4 lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing is characterized in that described hypersitization medicine makes one of following dosage form:
1. injection; 2. tablet; 3. capsule; 4. granule; 5. slow releasing agent.
6. the application of couplet benzene ring octadiene as claimed in claim 1 lignanoid in the hypersitization medicine of preparation tyrosine-kinase enzyme inhibitor thing is characterized in that described hypersitization medicine is the monomer or the mixture of described couplet benzene ring octadiene lignanoid.
CN2006100489051A 2006-01-05 2006-01-05 Application of dibenzocyclootadiene lignans in preparation of tyrosine-inhibiting medicine Expired - Fee Related CN1994289B (en)

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CN1621037A (en) * 2003-11-29 2005-06-01 胡汛 Application of Schisandrin-B in preparing medicine for treating tumor
CN1634854A (en) * 2004-12-08 2005-07-06 肖培根 Novel dibenzocyclooctenes lignan and its preparation method and use
CN1660067A (en) * 2004-12-01 2005-08-31 普尔药物科技开发（深圳）有限公司 Application of liganans of biphenyl cyelo-octadiene in preparing antineoplastic medicine

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CN1621037A (en) * 2003-11-29 2005-06-01 胡汛 Application of Schisandrin-B in preparing medicine for treating tumor
CN1660067A (en) * 2004-12-01 2005-08-31 普尔药物科技开发（深圳）有限公司 Application of liganans of biphenyl cyelo-octadiene in preparing antineoplastic medicine
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